The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of proteins and other biomolecules associated with target diseases. One important class of these proteins is the sigma (C) receptor, a cell surface receptor of the central nervous system (CNS) which may be related to the dysphoric, hallucinogenic and cardiac stimulant effects of opioids. From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J. M. et al, Pharmacological Reviews, 1990, 42, 355). It has been reported that the known sigma receptor ligand rimcazole clinically shows effects in the treatment of psycosis (Snyder, S. H., Largent, B. L. J. Neuropsychiatry 1989, 1, 7). The sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol.
The sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs. SKF 10047 has nanomolar affinity for the sigma 1 (σ-1) site, and has micromolar affinity for the sigma (σ-2) site. Haloperidol has similar affinities for both subtypes. Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them. Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci., 1992, 13:85-86). Most studies have implied that sigma binding sites (receptors) are plasmalemmal elements of the signal transduction cascade. Drugs reported to be selective sigma ligands have been evaluated as antipsychotics (Hanner, M. et al. Proc. Natl. Acad. Sci., 1996, 93:8072-8077). The existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
In view of the potential therapeutic applications of agonists or antagonists of the sigma receptor, a great effort has been directed to find selective ligands. Thus, the prior art discloses different sigma receptor ligands.
International Patent Application No WO 91/09594 generically describes a broad class of sigma receptor ligands some of which are 4-phenylpiperidine, -tetrahydro-pyridine or -piperazine compounds having an optionally substituted aryl or heteroaryl, alkyl, alkenyl, alkynyl, alkoxy or alkoxyalkyl substituent on the ring N-atom. The terms aryl and heteroaryl are defined by mention of a number of such substituents.
With regard to the chemical structure of the compounds described in the present patent application, it is to be highlighted that the 1,2,3-triazole ring system has been the subject of considerable research mainly due to the pharmacological properties shown by some of its derivatives and also because of its usefulness in synthetic organic chemistry. Among the first, recent reports have dealt with 1,2,3-triazoles as antimicrobial agents, as potassium channel activators (Calderone, V. et al. Eur. J. Med. Chem., 2005, 40, 521-528). 1,2,3-Triazole derivatives of glycosyl and galactoside have been respectively described as glycosidase (Rossi, L. L. et al., Bioorg. Med. Chem. Lett., 2005, 15, 3596-3599) and galactin-3 (Salameh, A. et al., Bioorg. Med. Chem. Lett., 2005, 15, 3344-3346) inhibitors. 2-Pyridinyl-1,2,3-triazoles have been described as transforming growth factor beta 1 type 1 receptor (Kim, J. et al, Bioorg. Med. Chem. Lett, 2004, 14, 2401-2405). In addition, a 1,2,3-triazole-4-carboxamide derivative (CAI) has been identified as an orally bioavailable calcium influx and signal transduction inhibitor with anti-angiogenic and anti-metastatic properties in different human tumours (Perabo, F. G., et al., Anticancer Res., 2005, 25, 725-729). The 1,2,3-triazole moiety has been identified as an effective replacement for a peptide group in HIV-1 protease inhibitors (Brik, J. et al., Chembiochem, 2005, 6, 1167-1169). Concerning synthetic issues, 1,2,3-triazoles can be considered the ideal representatives of “click chemistry” (Kolb, C. et al., Angew. Chem. Int. Edit., 2001, 40, 2004-2021), and recently, 1,2,3-triazole has been used as a safer and practical alternative to cyanide in Bruylants reaction (Prashad M. et al., Tetrahedron Lett., 2005, 46, 5455-5458).
However, none of these documents suggests the effect of these compounds on the sigma receptor.
There is still a need to find compounds that have pharmacological activity towards the sigma receptor, being both effective and selective, and having good “drugability” properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion.